Spinal cord injury (SCI) induces several destructive events that develop immediately after the primary insult. These phenomena increase tissue damage; that is why, numerous therapeutic approaches are studied in order to neutralize these destructive mechanisms. In line with this, several studies indicate that after injury, neural tissue could be protected by an adaptive immune response directed against self-antigens. Immunization with neural-derived peptides (INDP) reduces secondary degeneration of neurons after spinal cord insult and promotes a significant motor recovery. The combination of antioxidants or other immunomodulatory peptides after SCI can improve the protective effect induced by INDP. INDP in acute SCI is a promising strategy, so further studies should be addressed to be able to formulate the best strategy.

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The incidence of asthma, a heterogeneous inflammatory disease affecting over 300 million people worldwide, continues to increase in developed countries. Human epithelial cells (ECs) express the alarmin-type cytokine thymic stromal lymphopoietin (TSLP) following tissue injury triggered by several environmental insults, which include allergens, smoke, pollutants, or other irritants. Furthermore, TSLP has an emerging but well-documented pathogenic role in asthma. TSLP has been called a “master switch” of allergic inflammation at the epithelial-dendritic cell (DC) interface, where it supports T helper 2 (Th2) inflammatory polarization and promotes the maintenance of Th2 memory responses. Therefore, targeting TSLP/TSLP-mediated signaling may represent an attractive therapeutic strategy for asthma. Several studies of anti-TSLP drugs are ongoing; the first-in-class anti-TSLP monoclonal antibody (mAb) tezepelumab, the immunoglobulin G1 antibody fragment CSJ117, or TSLP-traps [a combination of anti-interleukin-13 (anti-IL-13) and anti-TSLP mAbs] all represent promising new treatment approaches. This article reviews the characteristics of TSLP and discusses the treatment of severe asthma through TSLP-associated mechanisms.

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Oxygen free radicals [reactive oxygen species (ROS)] and nitrogen free radicals [reactive nitrogen species (RNS)] are generated by mitochondria during adenosine triphosphate synthesis, and catalytic activities of cytochrome P450, nicotinamide adenine dinucleotide phosphate oxidases (NOXs), cyclooxygenases, and nitric oxide synthases during drug catabolism, phagocytosis, and acute inflammation. Under normal circumstances, low levels of ROS and RNS provide redox signalings that control many essential physiological processes. As age progresses ROS and RNS increase excessively due to dysfunctional mitochondria, dysregulated NOX, and other free-radical generating sources, leading to oxidative stress, which causes oxidation and denaturation of key cellular components including DNA, proteins, and lipids, which become abnormal, constituting damage-associated molecular pattern (DAMP), recognized as ‘non-self’ by immune cells, leading to inflammation which is mediated by nuclear factor kappa B-inflammasome, p38-c-Jun N-terminal kinase and Janus kinase-signal transducer and activator of transcription pathways. DAMPs are continuously released from damaged and senescent cells, causing an otherwise normally transient inflammation turning into systemic chronic inflammation, the root cause of aging and age-associated diseases (AADs). Cells restore redox balance by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway that induces the synthesis and release of antioxidation molecules and enzymes including haem oxygenase-1, which also inhibits the three inflammatory pathways. Furthermore, upregulation of autophagy (AP) can get rid of abnormal molecules, prevent the generation of DAMPs, and attenuate inflammation. Both AP and Nrf2 signalings decrease with age. The upregulations of Nrf2, AP, and downregulation of inflammation are controlled by sensors of energy and stress levels, i.e., adenosine monophosphate-activated protein kinase, silent information regulator 1, and Sestrins, as well as the extracellular matrix, while mammalian targets for rapamycin complex 1, a nutrient sensor, act in the opposite direction. If the balance of these sensor systems becomes dysregulated, aging process accelerates, and the risk of AADs increases.

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Hereditary cholestasis comprises a broad spectrum of clinical phenotypes of varying severity. Severe forms such as progressive familial intrahepatic cholestasis (PFIC) mostly affect children with disease onset within their first years. Nevertheless, late-onset PFIC forms are increasingly diagnosed. Most adults present with less severe forms of hereditary cholestasis, often suffering from pruritus, gallstone disease, jaundice, or elevated liver enzymes. To identify the underlying genetic background and to rule out potential differential diagnoses, a broad genetic analysis like whole exome sequencing (WES) is recommended. Knowledge of the affected gene may have an impact not only on patient surveillance due to risk for disease progression or tumor development but also on potential therapeutic strategies. This case of the adult patient illustrates the importance of broad genetic analysis, which brought up the potentially relevant rare multidrug resistance protein 3 (MDR3) missense variant p.(Asn489Tyr) underlying the patient’s clinical phenotype of low phospholipid-associated cholelithiasis (LPAC). Patients with MDR3 disease may have an increased risk for cholangiocarcinoma (CCA) development and therefore need an individualized surveillance strategy. Most MDR3-affected patients benefit from life-long therapy with ursodeoxycholic acid (UDCA), which is well tolerated. Bezafibrate treatment can reduce pruritus, one of the main symptoms affecting the quality of life. Whether the administration of ileal bile acid transporter (IBAT) inhibitors is beneficial in adult patients with MDR3 disease is so far unknown.

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The Raf kinase inhibitor protein (RKIP) has been reported to be underexpressed in many cancers and plays a role in the regulation of tumor cells' survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, is either mutated, underexpressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. The transcriptional and posttranscriptional regulations of RKIP and PTEN expressions and their roles in resistance were reviewed. The underlying mechanism of the interrelationship between the signaling expressions of RKIP and PTEN in cancer is not clear. Several pathways are regulated by RKIP and PTEN and the transcriptional and post-transcriptional regulations of RKIP and PTEN is significantly altered in cancers. In addition, RKIP and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In addition, molecular and bioinformatic data revealed crosstalk signaling networks that regulate the expressions of both RKIP and PTEN. These crosstalks involved the mitogen-activated protein kinase (MAPK)/PI3K pathways and the dysregulated nuclear factor-kappaB (NF-κB)/Snail/Yin Yang 1 (YY1)/RKIP/PTEN loop in many cancers. Furthermore, further bioinformatic analyses were performed to investigate the correlations (positive or negative) and the prognostic significance of the expressions of RKIP or PTEN in 31 different human cancers. These analyses were not uniform and only revealed that there was a positive correlation between the expression of RKIP and PTEN only in few cancers. These findings demonstrated the existence of signaling cross-talks between RKIP and PTEN and both regulate resistance. Targeting either RKIP or PTEN (alone or in combination with other therapies) may be sufficient to therapeutically inhibit tumor growth and reverse the tumor resistance to cytotoxic therapies.

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Tannins are secondary metabolites that belong to the family of polyphenolic compounds and have gained a huge interest among researchers due to their versatile therapeutic potential. After lignin, these are the second most abundant polyphenols found in almost every plant part like stem, bark, fruit, seed, leaves, etc. Depending upon their structural composition, these polyphenols can be divided into two distinct groups, namely condensed tannins and hydrolysable tannins. Hydrolysable tannins can be further divided into two types: gallotannins and ellagitannins. Gallotannins are formed by the esterification of D-glucose hydroxyl groups with gallic acid. The gallolyl moieties are bound by a depside bond. The current review focuses mainly on the anti-carcinogenic potential of recently discovered gallotannins, ginnalin A, and hamamelitannin (HAM). Both of these gallotannins possess two galloyl moieties linked to a core monosaccharide having anti-oxidant, anti-inflammatory, and anti-carcinogenic abilities. Ginnalin A is found in plants of the genus Acer whereas HAM is present in witch hazel plants. The biosynthetic pathway of ginnalin A along with the mechanism of the anti-cancer therapeutic potential of ginnalin A and HAM has been discussed. This review will certainly help researchers to work further on the chemo-therapeutic abilities of these two unique gallotannins.

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Despite decades of intensive research, effective treatment and prevention strategies for neurodegenerative diseases (NDDs) remain elusive. This review focuses on Alzheimer’s and Parkinson’s diseases and acquired epilepsy suggesting that in their early phase, these progressive pathologies share common or interacting molecular pathways. Indeed, oxidative stress associated with disrupted glucose metabolism is the expected end state of most, if not all, risk factors preceding the onset of major NDDs. This review proposes that the initial oxidative stress in the brain resulting specifically from the hyperactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) causes a decline in glucose utilization and is the primary initiating factor of major NDDs. The existing clinical and experimental evidence points to NOX as the primary initiating mechanism shared within the major NDDs. During early oxidative stress, NOX activation is triggered in variable brain cells via multiple pathways, from beta-amyloid to alpha-synuclein, fibrin to glutamate and seizures. Therefore, the treatment strategy should have targeted the activation of NOX, wouldn’t there be a lack of clinically approved selective NOX antagonists? On the other hand, there are promising metabolism-altering approaches via dietary means able to switch energy intake from glucose to ketones, which influences both oxidative stress and glucose utilization and could ameliorate disease progression. The regimen of time-restricted eating appears to be the most feasible, nutritious, and palatable one providing the essential benefits of a ketogenic diet without adverse effects.

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Esophageal squamous cell carcinoma (ESCC) is the second leading cause of cancer-related deaths in Iran, often diagnosed in advanced stages with a poor prognosis. Growth and differentiation factor 3 (GDF3) is a member of the transforming growth factor-beta (TGF-β) superfamily. It acts as an inhibitor of bone morphogenetic proteins (BMPs) signaling pathway associated with pluripotent embryonic and cancer stem cells (CSCs) characteristics. Since its expression in ESCC has not yet been evaluated, the clinicopathological relevance of GDF3 expression was elucidated in ESCC patients. Expression of GDF3 in tumor tissues from 40 ESCC patients was compared to the related margin normal tissues by relatively comparative real-time polymerase chain reaction (PCR). Glyceraldehydes 3-phosphate dehydrogenase (GAPDH) was used as the endogenous control. Likewise, the function of GDF3 in the differentiation and development of embryonic stem cells (ESCs) was also reviewed. GDF3 was significantly overexpressed in 17.5% of tumors and a significant correlation between GDF3 expression and the depth of tumor invasion was observed (P = 0.032). The results suggest that GDF3 expression is likely to have substantial roles in the progression and invasiveness behavior of ESCC. Having considered the importance of CSC markers identification and their exploitation in targeted cancer therapy, GDF3 may be introduced as a promising therapeutic target to inhibit the invasion of tumor cells in ESCC.

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In the last years, multiple efforts have been made to accurately predict neoantigens derived from somatic mutations in cancer patients, either to develop personalized therapeutic vaccines or to study immune responses after cancer immunotherapy. In this context, the increasing accessibility of paired whole-exome sequencing (WES) of tumor biopsies and matched normal tissue as well as RNA sequencing (RNA-Seq) has provided a basis for the development of bioinformatics tools that predict and prioritize neoantigen candidates. Most pipelines rely on the binding prediction of candidate peptides to the patient’s major histocompatibility complex (MHC), but these methods return a high number of false positives since they lack information related to other features that influence T cell responses to neoantigens. This review explores available computational methods that incorporate information on T cell preferences to predict their activation after encountering a peptide-MHC complex. Specifically, methods that predict i) biological features that may increase the availability of a neopeptide to be exposed to the immune system, ii) metrics of self-similarity representing the chances of a neoantigen to break immune tolerance, iii) pathogen immunogenicity, and iv) tumor immunogenicity. Also, this review describes the characteristics of these tools and addresses their performance in the context of a novel benchmark dataset of experimentally validated neoantigens from patients treated with a melanoma vaccine (VACCIMEL) in a phase II clinical study. The overall results of the evaluation indicate that current tools have a limited ability to predict the activation of a cytotoxic response against neoantigens. Based on this result, the limitations that make this problem an unsolved challenge in immunoinformatics are discussed.

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The gastrointestinal (GI) microbiome remains an emerging topic of study and the characterization and impact on human health and disease continue to be an area of great interest. Similarly, the coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the healthcare system with active disease, lasting effects, and complications with the full impact yet to be determined. The most current evidence of the interaction between COVID-19 and the GI microbiome is reviewed, with a focus on key mediators and the microbiome changes associated with acute disease and post-acute COVID-19 syndrome (PACS).

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DNA paralogs that have a length of at least 1 kilobase (kb) and are duplicated with a sequence identity of over 90% are classified as low copy repeats (LCRs) or segmental duplications (SDs). They constitute 6.6% of the genome and are clustering in specific genomic loci. Due to the high sequence homology between these duplicated regions, they can misalign during meiosis resulting in non-allelic homologous recombination (NAHR) and leading to structural variation such as deletions, duplications, inversions, and translocations. When such rearrangements result in a clinical phenotype, they are categorized as a genomic disorder. The presence of multiple copies of larger genomic segments offers opportunities for evolution. First, the creation of new genes in the human lineage will lead to human-specific traits and adaptation. Second, LCR variation between human populations can give rise to phenotypic variability. Hence, the rearrangement predisposition associated with LCRs should be interpreted in the context of the evolutionary advantages.

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The novel coronavirus disease-2019 (COVID-19) has created a major public health crisis. Various dietary factors may enhance immunological activity against COVID-19 and serve as a method to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The dietary factors that are responsible for boosting immunity may provide a therapeutic advantage in patients with COVID-19. Investigators have demonstrated that vitamins B6, B12, C, D, E, and K, and trace elements like zinc, copper, selenium, and iron may serve as important tools for immunomodulation. Herein this is a review the peer-reviewed literature pertaining to dietary immunomodulation strategies against COVID-19. This review is intended to better define the evidence that dietary modifications and supplementation could positively influence the proinflammatory state in patients with COVID-19 and improve clinical outcomes. With appropriate insight, therapeutic interventions are discussed and directed to potentially modulate host immunity to mitigate the disease mechanisms of COVID-19.

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